This is generally in the field of polymeric materials for modulation of cell to cell interactions, especially for biomedical applications.
Hydrogels as Controlled-release Carriers
Biodegradable hydrogels can be carriers for biologically active materials such as hormones, enzymes, antibiotics, antineoplastic agents, and cell suspensions. Temporary preservation of functional properties of a carried species, as well as controlled release of the species into local tissues or systemic circulation, are possible. Proper choice of hydrogel macromers can produce membranes with a range of permeability, pore sizes and degradation rates suitable for a variety of applications in surgery, medical diagnosis and treatment.
Adhesives and Sealers
Polymeric hydrogels have also been used as tissue adhesives and sealants. Fibrin gels have been used extensively in Europe as sealants and adhesives in surgery (Thompson et al., 1988, Drug Intell. and Clin. Pharm., 22:946; Gibble et al., 1990, (1990), Transfusion, 30(8):741). Synthetic polymers have been explored as adhesives (Lipatova, 1986, Advances in Polymer Science 79:65-93), but these materials have generally been associated with local inflammation, cytotoxicity, and poor biocompatability.
Prevention of Postoperative Adhesions.
Formation of post-surgical adhesions involving organs of the peritoneal cavity and the peritoneal wall is a frequent and undesirable result of abdominal surgery. Surgical trauma to the tissue caused by handling and drying results in release of a serosanguinous (proteinaceous) exudate which tends to collect in the pelvic cavity (Holtz, G., 1984). If the exudate is not absorbed or lysed within this period it becomes ingrown with fibroblasts, and subsequent collagen deposition leads to adhesion formation.
Numerous approaches to elimination of adhesion formation have been attempted, with limited success in most cases. Approaches have included lavage of the peritoneal cavity, administration of pharmacological agents, and the application of barriers to mechanically separate tissues. However, none of these approaches has been cost effective and effective in in vivo studies. Solutions of Poloxamer 407 have been used for the treatment of adhesions, with some success. Poloxamer is a copolymer of ethylene oxide and propylene oxide and is soluble in water; the solutions are liquids at room temperature. Steinleitner et al. (1991) Obstetrics and Gynecology, 77(1):48 and Leach et al. (1990) Am. J. Obstet. Gynecol., 162(5):1317, examined Poloxamer solutions in peritoneal adhesion models and observed statistically significant reductions in adhesions; however, they were unable to eliminate adhesions, perhaps because of limited adhesion and retention on the injury site. Oxidized regenerated cellulose has also been used extensively to prevent adhesions and is an approved clinical product, trade-named Interceed TC7. This barrier material has been shown to be somewhat effective in rabbits (Linsky et al., 1987 J. Reprod. Med., 32:17; Diamond et al., 1987 Microsurgery, 8:103) and in humans (Interceed (TC7) Adhesion Barrier Study Group, 1989). It was shown to be more effective if pretreated with heparin, but was still unable to completely eliminate adhesions (Diamond et al., 1991 xe2x80x9cFertility and Sterility, 55(2):389). U.S. Pat. No. 5,410,016 to Hubbell, et al., describes photopolymerizable biodegradable hydrogels as tissue contacting materials and controlled release carriers. These polymers included a water soluble region flanked by biodegradable linkers, terminated in photopolymerizable groups. Despite promising results in a rabbit model of adhesions, results of clinical trials to prevent adhesions following Cesarean sections were mixed, perhaps due to insufficient polymer thickness of the layers.
It is an object of the present invention to provide polymeric materials which form gels, coatings, and multi-layer structures that are bioinert and therefore useful for a variety of biomedical applications, including prevention of adhesions, as sealants, and for controlled delivery.
It is another object of the present invention to provide means for applying these polymeric materials to form coatings and medical devices.
Boronic acid containing polymers are used to form bioinert gels and multilayer surface structures. These polymers form crosslinked hydrogels, which are highly swollen in water. The crosslinking can either be chemical or physical. Water soluble polymers containing boronic acid groups, such as phenylboronic acid (PBA), can be physically crosslinked by mixing the polymers in water with other polymers containing hydroxyls or carboxylic acids. Alternatively, surfaces can be treated by stepwise incubation with a solution of the boronic acid containing polymer, followed by incubation with a solution of a diol or carboxylic acid containing polymer. Many successive layers can be generated, increasing the thickness of the formed structure at each step. Treatment of the surface is dependent upon the surface activity of the boronate containing polymer or the diol or carboxylic acid containing polymer, or the use of a priming layer, consisting of a molecule which has an affinity for the surface, as well as an affinity for the boronate containing polymer or the diol or carboxylic acid containing polymer. Priming may not be necessary in the case of binding to a cell or tissue surface, because the boronic acid domains bind to diols present in glycosylated proteins present in the cells.
The bioinert gel or surface coating can be used for passivating the surfaces of medical implants (especially those based on transplanted tissue), or for passivating the surfaces of tissues in situ, decreasing the incidence or severity of such pathologic conditions as the formation of post-surgical adhesions, and thrombosis following angioplasty.